Decreased Right Ventricular Function in a Novel Model of Pulmonary Insufficiency in Rat

The population of adult patients with right ventricular (RV) dysfunction is increasing due in part to the increasing number of children with corrected congenital heart defects that now survive to adulthood. We have developed a novel model of pulmonary insufficiency (PI) to investigate the time course of right ventricular failure due to volume loading. Methods: PI was created in Sprague-Dawley rats by disrupting the pulmonary valve. After a limited thoracotomy, a custom made hook was inserted through the RV apex into the RV-pulmonary artery annulus and moved back and forth several times to disrupt the valve. After 16-18 weeks, function was assessed by echocardiography (Visualsonics 2100) and RV function was measured using a Langendorff isolated heart system. Results: Evidence of PI was noted by regurgitant flow using color Doppler. There was no difference in RV weight or left ventricular function by echo between the sham and PI groups. Tricuspid annular plane systolic excursion (TAPSE) was significantly lower in PI compared to sham (2.46±0.19, n=8 vs. 3.16±0.13, n=5, p<0.05) indicating diminished RV function. Furthermore, in isolated hearts, developed pressure (DP) was significantly smaller in PI compared to sham (25.5±2.7, n=9 vs. 36.5±3.6 mmHg, n=5, p<0.05) as was the minimum derivative of pressure (dPmin, -500±46, n=9 vs. -731±81 mmHg/s, n=5, p<0.02). We separated the PI group into mild-PI and moderate-PI based on the amount of regurgitant flow. Isolated hearts were perfused with dobutamine to determine RV functional reserve. For the sham group, there was a dose-dependent increase of DP in response to dobutamine (36.5±3.6 vs. 38.0±1.7 vs. 51.2±4.1 mmHg for baseline, 100 nM, and 1 μ M (n=5), p<0.05 for 1 μ M vs. baseline and 100 nM). Similar results were found for dPmin and dPmax. In contrast, dobutamine did not significantly increase any functional parameters in the mild or moderate-PI groups. Conclusions: Disruption of the pulmonary valve in a rat model caused mild to moderate PI. Measures of RV function (TAPSE and DP) were decreased in the PI group. Response to dobutamine was robust in the sham group and diminished in both mild and moderate PI groups. This is a novel model of PI that can be used to investigate the mechanisms of RV failure in response to volume overload.